Adventures with the ß2-adrenoceptor Receptor: A Career Long Interest in Agonising One of the Most Widely Studied GPCRs.

Drug discovery is a multi-disciplinary effort in which groups with expertise in a range of areas combine in a unified way to achieve a common goal: to deliver a clinical candidate to evaluate a hypothesis for improving human health. As a medicinal chemist this environment has provided multiple opportunities to be involved in cross-discipline interactions that have been both rewarding and led to outcomes that would not have been possible without an intimate interdisciplinary curiosity. Within this article I aim to share some of my experiences with the ß2-adrenoceptor that have fostered such synergistic relationships with several disciplines, but in particular with in vitro pharmacologists looking at different ways to stimulate this G protein-coupled receptor (GPCR). This interest now spans over a quarter of a century and has been intertwined with the delivery of three clinical candidates.

Social entrepreneurship and public health nursing knowledge: Opportunities for innovating nursing education in population health.

Public health nursing (PHN) competencies are fundamental for addressing population health inequities. Few pathways exist for employing these competencies in the United States (US). Social entrepreneurship in nursing education might provide opportunities for innovating engagement in population health. Partnerships between business and nursing schools have the potential to fulfill this opportunity. PURPOSE: Explore opportunities for re-invigorating public health nursing through social entrepreneurship education in nursing-business partnerships in U.S. universities. METHODS: Reviewed programs in nursing/business school partnerships from Carnegie-classified R1 Universities. Identified appropriate coursework. RESULTS: Of 96 identified nursing schools, eight had business school partnerships, providing 12 programs. Most programs (n = 11) targeted graduate students and addressed core competencies for entrepreneurship. Five business schools had entrepreneurship expertise. Five nursing schools had PHN expertise. Three programs included population health competencies. DISCUSSION: Despite missed opportunities for advancing social entrepreneurship education among undergraduate and graduate nursing students, existing curricular offerings in the partnerships provide promise. Business/nursing partnerships and PHN knowledge can stimulate the preparation and agency of nurses in addressing population health inequities.

Information search under uncertainty across transdiagnostic psychopathology and healthy ageing.

When making decisions in everyday life, we often rely on an internally generated sense of confidence to help us revise and direct future behaviours. For instance, confidence directly informs whether further information should be sought prior to commitment to a final decision. Many studies have shown that aging and both clinical and sub-clinical symptoms of psychopathology are associated with systematic alterations in confidence. However, it remains unknown whether these confidence distortions influence information-seeking behaviour. We investigated this question in a large general population sample (N = 908). Participants completed a battery of psychiatric symptom questionnaires and performed a perceptual decision-making task with confidence ratings in which they were offered the option to seek helpful information (at a cost) before committing to a final decision. Replicating previous findings, an 'anxious-depression' (AD) symptom dimension was associated with systematically low confidence, despite no detriment in objective task accuracy. Conversely, a 'compulsive behaviour and intrusive thoughts' (CIT) dimension was associated with impaired task accuracy but paradoxical over-confidence. However, neither symptom dimension was significantly associated with an increased or decreased tendency to seek information. Hence, participants scoring highly for AD or CIT did not use the option to information seek any more than average to either increase their confidence (AD) or improve the accuracy of their decisions (CIT). In contrast, older age was associated with impaired accuracy and decreased confidence initially, but increased information seeking behaviour mediated increases in both accuracy and confidence for final decisions. Hence, older adults used the information seeking option to overcome initial deficits in objective performance and to increase their confidence accordingly. The results show an appropriate use of information seeking to overcome perceptual deficits and low confidence in healthy aging which was not present in transdiagnostic psychopathology.

High-quality lipid suppression and B0 shimming for human brain 1H MRSI.

Magnetic Resonance Spectroscopic Imaging (MRSI) is a powerful technique that can map the metabolic profile in the brain non-invasively. Extracranial lipid contamination and insufficient B0 homogeneity however hampers robustness, and as a result has hindered widespread use of MRSI in clinical and research settings. Over the last six years we have developed highly effective extracranial lipid suppression methods with a second order gradient insert (ECLIPSE) utilizing inner volume selection (IVS) and outer volume suppression (OVS) methods. While ECLIPSE provides > 100-fold in lipid suppression with modest radio frequency (RF) power requirements and immunity to B1+ field variations, axial coverage is reduced for non-elliptical head shapes. In this work we detail the design, construction, and utility of MC-ECLIPSE, a pulsed second order gradient coil with Z2 and X2Y2 fields, combined with a 54-channel multi-coil (MC) array. The MC-ECLIPSE platform allows arbitrary region of interest (ROI) shaped OVS for full-axial slice coverage, in addition to MC-based B0 field shimming, for robust human brain proton MRSI. In vivo experiments demonstrate that MC-ECLIPSE allows axial brain coverage of 92-95 % is achieved following arbitrary ROI shaped OVS for various head shapes. The standard deviation (SD) of the residual B0 field following SH2 and MC shimming were 25 ± 9 Hz and 18 ± 8 Hz over a 5 cm slab, and 18 ± 5 Hz and 14 ± 6 Hz over a 1.5 cm slab, respectively. These results demonstrate that B0 magnetic field shimming with the MC array supersedes second order harmonic capabilities available on standard MRI systems for both restricted and large ROIs. Furthermore, MC based B0 shimming provides comparable shimming performance to an unrestricted SH5 shim set for both restricted, and 5-cm slab shim challenges. Phantom experiments demonstrate the high level of localization performance achievable with MC-ECLIPSE, with ROI edge chemical shift displacements ranging from 1-3 mm with a median value of 2 mm, and transition width metrics ranging from 1-2.5 mm throughout the ROI edge. Furthermore, MC based B0 shimming is comparable to performance following a full set of unrestricted spherical harmonic fields up to order 5. Short echo time MRSI and GABA-edited MRSI acquisitions in the human brain following MC-shimming and arbitrary ROI shaping demonstrate full-axial slice coverage and extracranial lipid artifact free spectra. MC-ECLIPSE allows full-axial coverage and robust MRSI acquisitions, while allowing interrogation of cortical tissue proximal to the skull, which has significant value in a wide range of neurological and psychiatric conditions.

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

Pharmacy Naloxone Standing Order and Community Opioid Fatality Rates Over Time.

Importance: Despite the proliferation of pharmacy standing-order naloxone dispensing across many US states before the change to over-the-counter status, few policy analyses have evaluated the implementation of pharmacy naloxone standing orders in addressing opioid overdose fatality among communities. Objective: To determine whether the implementation of pharmacy standing-order naloxone was associated with lower opioid fatality rates compared with communities without pharmacies with standing-order naloxone. Design, Setting, and Participants: This retrospective multisite study was conducted with an interrupted time series analysis across 351 municipalities in Massachusetts over 24 quarters (from January 1, 2013, through December 31, 2018). Standing-order naloxone dispensing data were collected from 2 sources for all major chain pharmacies and many independent pharmacies, covering 70% of retail pharmacies in Massachusetts. Municipalities had various standing-order naloxone implementation inceptions during the study period. Data were analyzed from December 2021 to November 2023. Exposure: The main exposure was measured by the first quarter with standing-order naloxone dispensation as the actual implementation inception. Main Outcomes and Measures: The primary study outcome was municipal opioid fatality rate per 100 000 population obtained from the Massachusetts Registry of Vital Records and Statistics. Results: The median (IQR) population size across 351 municipalities was 10 314 (3635 to 21 781) people, with mean (SD) proportion of female individuals was 51.1% (2.8 percentage points). Pharmacies from 214 municipalities (60.9%) reported dispensing standing-order naloxone over the study period. At the baseline of the first quarter of 2013, municipalities that eventually had standing-order naloxone had greater quarterly opioid fatality rates compared with those that never implemented standing-order naloxone (3.51 vs 1.03 deaths per 100 000 population; P < .001). After adjusting for municipal-level sociodemographic and opioid prevention factors, there was significant slope decrease of opioid fatality rates (annualized rate ratio, 0.84; 95% CI, 0.78-0.91; P < .001) following standing-order naloxone dispensing, compared with the municipalities that did not implement standing-order naloxone. There were no significant level changes of opioid fatality rates in the adjusted models. Sensitivity analyses yielded similar and significant findings. Conclusions and Relevance: These findings suggest that community pharmacy dispensing of naloxone with standing orders was associated with a relative, gradual, and significant decrease in opioid fatality rates compared with communities that did not implement the standing-order naloxone program. These findings support the expansion of naloxone access, including over-the-counter naloxone as part of a multifaceted approach to address opioid overdose.

Nuclear poly-glutamine aggregates rupture the nuclear envelope and hinder its repair.

Huntington's disease (HD) is caused by a polyglutamine expansion of the huntingtin protein, resulting in the formation of polyglutamine aggregates. The mechanisms of toxicity that result in the complex HD pathology remain only partially understood. Here, we show that nuclear polyglutamine aggregates induce nuclear envelope (NE) blebbing and ruptures that are often repaired incompletely. These ruptures coincide with disruptions of the nuclear lamina and lead to lamina scar formation. Expansion microscopy enabled resolving the ultrastructure of nuclear aggregates and revealed polyglutamine fibrils sticking into the cytosol at rupture sites, suggesting a mechanism for incomplete repair. Furthermore, we found that NE repair factors often accumulated near nuclear aggregates, consistent with stalled repair. These findings implicate nuclear polyQ aggregate-induced loss of NE integrity as a potential contributing factor to Huntington's disease and other polyglutamine diseases.

ECTOPIC trial: The efficacy of flEcainide Compared To metOprolol in reducing Premature ventrIcular Contractions: A randomized open-label crossover study in pediatric patients.

BACKGROUND: Frequent premature ventricular contractions (PVCs) in children are usually considered benign. Symptoms and left ventricular dysfunction are indications for treatment with antiarrhythmic drugs. OBJECTIVE: This study aimed to evaluate the efficacy of flecainide vs metoprolol in reducing PVCs in children. METHODS: A randomized open-label crossover trial was conducted of children with a PVC burden of >15% on Holter monitoring successively treated with metoprolol and flecainide, or vice versa, with a drug-free interval of at least 2 weeks. Holter measurements were repeated before and after the start of the antiarrhythmic drug. RESULTS: Sixty patients were screened; 19 patients could be included. Median age was 13.9 years (interquartile range, 5.5 years). Mean baseline PVC burden was 21.7% (n = 18; SD ± 14.0) before the start of flecainide and 21.2% (n = 17; SD ± 11.5) before the start of metoprolol. In a mixed model analysis, the estimated mean reduction in PVC burden was 10.6 percentage points (95% CI, 5.8-15.3) for flecainide and 2.4 percentage points (95% CI,2.7-7.5) for metoprolol, with a significant difference of 8.2 percentage points (95% CI, 0.86-15.46; P = .031). Exploratory analysis revealed that 9 of 18 patients treated with flecainide and 1 of 17 patients treated with metoprolol had a reduction to a PVC burden below 5%. No discriminating factors between flecainide responders and nonresponders were found; the mean plasma level was not significantly different (0.34 mg/L vs 0.52 mg/L; P = .277). CONCLUSION: In children with frequent PVCs, flecainide led to a significantly greater reduction of PVC burden compared with metoprolol. Flecainide was effective in only a subgroup of patients, which appears to be unrelated to the plasma level.

Menopause and Traumatic Brain Injury: A NIDILRR Collaborative Traumatic Brain Injury Model Systems Study.

OBJECTIVE: To examine the experience of menopause symptoms in women with traumatic brain injury (TBI). DESIGN: Cross-sectional descriptive study. SETTING: Five sites of the TBI Model Systems (TBIMS) program. PARTICIPANTS: Participants were 210 women, aged 40-60 years, who were not taking systemic hormones and did not have both ovaries removed: 61 participants were enrolled in the TBIMS, who were at least 2 years post-TBI and living in the community. One hundred forty-nine participants without TBI were recruited from a research registry and the metropolitan Detroit community. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: A checklist comprised of 21 menopause symptoms assessing 4 symptom clusters (vasomotor, somatic, psychological, and cognitive). RESULTS: TBI and non-TBI groups did not significantly differ and showed small effect sizes on vasomotor symptoms. On the remaining symptom clusters, women with TBI showed greater presence and severity of symptoms than women without TBI, as well as fewer differences between premenopausal and postmenopausal women on those symptoms. A profile indicating an additive or potentiating effect of TBI on menopause symptoms was not observed. CONCLUSIONS: Findings support a conceptual model of menopause and TBI indicating that symptoms most closely associated with estrogen decline are similar for women with and without TBI, whereas symptoms that overlap with common TBI sequelae are generally more frequent and severe among these women. Likely because of lower baseline of symptoms premenopause, postmenopausal women without TBI reported more numerous and severe symptoms relative to their premenopausal counterparts without TBI. Overall, it may be that women without TBI experience menopause as more of a "change" of life, whereas women with TBI chronically face significantly more of these symptoms than women without TBI.

Indocyanine green near-infrared fluorescence bowel perfusion assessment to prevent anastomotic leakage in minimally invasive colorectal surgery (AVOID): a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Anastomotic leakage is a severe postoperative complication in colorectal surgery and compromised bowel perfusion is considered a major contributing factor. Conventional methods to assess bowel perfusion have a low predictive value for anastomotic leakage. We therefore aimed to evaluate the efficacy of real-time assessment with near-infrared (NIR) fluorescence imaging with indocyanine green (ICG) in the prevention of anastomotic leakage. METHODS: This multicentre, randomised, controlled, phase 3 trial was done in eight hospitals in the Netherlands. We included adults (aged >18 years) who were scheduled for laparoscopic or robotic colorectal surgery (with planned primary anastomosis) for benign and malignant diseases. Preoperatively, patients were randomly assigned (1:1) to fluorescence-guided bowel anastomosis (FGBA) or conventional bowel anastomosis (CBA) by variable block randomisation (block sizes 4, 6, and 8) and stratified by site. The operating surgeon and investigators analysing the data were not masked to group assignment. Patients were unmasked after the surgical procedure or after study end. In the FGBA group, surgeons marked anastomosis levels per conventional perfusion assessment and then administered 5 mg of ICG by 2 mL intravenous bolus. They assessed bowel perfusion using NIR fluorescence imaging and adjusted (or kept) transection lines accordingly. Only conventional methods for bowel perfusion assessment were used in the CBA group. The primary outcome was the difference in the rate of clinically relevant anastomotic leakage (ie, requiring active therapeutic intervention but manageable without reoperation [grade B] or requiring reoperation [grade C], per the International Study Group of Rectal Cancer) between the FGBA group and the CBA group within 90 days post-surgery. The primary outcome and safety were assessed in the intention-to-treat population. This study was registered with ToetsingOnline.nl (NL7502) and ClinicalTrials.gov (NCT04712032) and is complete. FINDINGS: Between July 2, 2020, and Feb 21, 2023, 982 patients were enrolled, of whom 490 were assigned to FGBA and 492 were assigned to CBA. After excluding 51 patients, the intention-to-treat population comprised 931 (463 assigned FGBA and 468 assigned CBA). Patients had a median age of 68·0 years (IQR 59·0-75·0) and 485 (52%) were male and 446 (48%) were female. Ethnicity data were not available. The overall 90-day rate of clinically relevant anastomotic leakage was not significantly different between the FGBA group (32 [7%] of 463 patients) and the CBA group (42 [9%] of 468 patients; relative risk 0·77 [95% CI 0·50-1·20]; p=0·24). No adverse events related to ICG use were observed. 313 serious adverse events in 229 (25%) patients were at 90-day follow-up (159 serious adverse events in 113 [24%] patients in the FGBA group and 154 serious adverse events in 116 [25%] patients in the CBA group). 18 (2%) people died by 90 days (ten in the FGBA group and eight in the CBA group). INTERPRETATION: ICG NIR fluorescence imaging did not reduce 90-day anastomotic leakage rates in this trial across all types of colorectal surgeries. Further research should be done in subgroups, such as rectosigmoid resections, for which evidence suggests ICG NIR might be beneficial. FUNDING: Olympus Medical, Diagnostic Green, and Intuitive Foundation.

Renal autocrine neuropeptide FF (NPFF) signaling regulates blood pressure.

The kidney and brain play critical roles in the regulation of blood pressure. Neuropeptide FF (NPFF), originally isolated from the bovine brain, has been suggested to contribute to the pathogenesis of hypertension. However, the roles of NPFF and its receptors, NPFF-R1 and NPFF-R2, in the regulation of blood pressure, via the kidney, are not known. In this study, we found that the transcripts and proteins of NPFF and its receptors, NPFF-R1 and NPFF-R2, were expressed in mouse and human renal proximal tubules (RPTs). In mouse RPT cells (RPTCs), NPFF, but not RF-amide-related peptide-2 (RFRP-2), decreased the forskolin-stimulated cAMP production in a concentration- and time-dependent manner. Furthermore, dopamine D1-like receptors colocalized and co-immunoprecipitated with NPFF-R1 and NPFF-R2 in human RPTCs. The increase in cAMP production in human RPTCs caused by fenoldopam, a D1-like receptor agonist, was attenuated by NPFF, indicating an antagonistic interaction between NPFF and D1-like receptors. The renal subcapsular infusion of NPFF in C57BL/6 mice decreased renal sodium excretion and increased blood pressure. The NPFF-mediated increase in blood pressure was prevented by RF-9, an antagonist of NPFF receptors. Taken together, our findings suggest that autocrine NPFF and its receptors in the kidney regulate blood pressure, but the mechanisms remain to be determined.

High phenotypic and genotypic plasticity among strains of the mushroom-forming fungus Schizophyllum commune.

Schizophyllum commune is a mushroom-forming fungus notable for its distinctive fruiting bodies with split gills. It is used as a model organism to study mushroom development, lignocellulose degradation and mating type loci. It is a hypervariable species with considerable genetic and phenotypic diversity between the strains. In this study, we systematically phenotyped 16 dikaryotic strains for aspects of mushroom development and 18 monokaryotic strains for lignocellulose degradation. There was considerable heterogeneity among the strains regarding these phenotypes. The majority of the strains developed mushrooms with varying morphologies, although some strains only grew vegetatively under the tested conditions. Growth on various carbon sources showed strain-specific profiles. The genomes of seven monokaryotic strains were sequenced and analyzed together with six previously published genome sequences. Moreover, the related species Schizophyllum fasciatum was sequenced. Although there was considerable genetic variation between the genome assemblies, the genes related to mushroom formation and lignocellulose degradation were well conserved. These sequenced genomes, in combination with the high phenotypic diversity, will provide a solid basis for functional genomics analyses of the strains of S. commune.

Drug Screening Using Normal Cell and Cancer Cell Mixture in an Automated 3D Cell Culture System.

Three-dimensional (3D) cell culture creates a more physiologically relevant environment for enhanced drug screening capabilities using microcarriers. An automated 3D system that integrates robotic manipulators, liquid handling systems, sensors, and environment control systems has the capacity to handle multiple samples in parallel, perform repetitive tasks, and provide real-time monitoring and analysis. This chapter describes a potential 3D cell culture drug screening model by combining renal proximal tubule cells as a representative normal cell line with cancer cell lines. This combination is subjected to drug screening to evaluate the drug's efficacy in suppressing cancer cells while minimizing impact on normal cells with the added benefit of having the ability to separate the two cell types by magnetic isolation for high content screens including mass spectrometry-based proteomics. This study presents advancements in 3D cell culture techniques, emphasizing the importance of automation and the potential of microcarriers in drug screening and disease modeling.

Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas.

Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.

Challenging Misconceptions about Race in Undergraduate Genetics.

Racial biases, which harm marginalized and excluded communities, may be combatted by clarifying misconceptions about race during biology lessons. We developed a human genetics laboratory activity that challenges the misconception that race is biological (biological essentialism). We assessed the relationship between this activity and student outcomes using a survey of students' attitudes about biological essentialism and color-evasive ideology and a concept inventory about phylogeny and human diversity. Students in the human genetics laboratory activity showed a significant decrease in their acceptance of biological essentialism compared with a control group, but did not show changes in color-evasive ideology. Students in both groups exhibited increased knowledge in both areas of the concept inventory, but the gains were larger in the human genetics laboratory. In the second iteration of this activity, we found that only white students' decreases in biological essentialist beliefs were significant and the activity failed to decrease color-evasive ideologies for all students. Concept inventory gains were similar and significant for both white and non-white students in this iteration. Our findings underscore the effectiveness of addressing misconceptions about the biological origins of race and encourage more research on ways to effectively change damaging student attitudes about race in undergraduate genetics education.

Modified Rankin Scale disability status at day 4 poststroke is an informative predictor of long-term day 90 outcome.

BACKGROUND: Long-term disability after stroke is standardly assessed 3 months post-onset, using the modified Rankin Scale (mRS). The value of an early, day 4 mRS assessment for projecting the 3-month disability outcome has not been formally investigated. METHODS: In this cohort of patients with acute cerebral ischemia and intracranial hemorrhage, we analyzed day 4 and day 90 mRS assessments in the NIH Field Administration of Stroke Therapy- Magnesium (FAST-MAG) Phase 3 trial. The performance of day 4 mRS, alone and as part of multivariate models, in predicting day 90 mRS was assessed using correlation coefficients, percent agreement, and the kappa statistics. RESULTS: Among the 1573 acute cerebrovascular disease (ACVD) patients, 1206 (76.7%) had acute cerebral ischemia (ACI), while 367 (23.3%) had intracranial hemorrhage. Among all 1573 ACVD patients, day 4 mRS and day 90 mRS correlated strongly, Spearman's rho=0.79, in unadjusted analysis with weighted kappa of 0.59. For dichotomized outcomes, simple carry-forward of the day 4 mRS performed fairly well in agreeing with day 90 mRS: mRS 0-1 (kappa=0.67), 85.4%; mRS 0-2 (k=0.59), 79.5%; fatal outcome, 88% (k=0.33). Correlations of 4d and 90d mRS were stronger for ACI than ICH patients, 0.76 vs 0.71. CONCLUSIONS: In this acute cerebrovascular disease patient cohort, assessment of global disability performed on day 4 is highly informative regarding long-term, 3-month mRS disability outcome, alone, and even more strongly in combination with baseline prognostic variables. The day 4 mRS is a useful measure for imputing the final patient disability outcome in clinical trials and quality improvement programs.

Pre-frontal cortex guides dimension-reducing transformations in the occipito-ventral pathway for categorization behaviors.

To interpret our surroundings, the brain uses a visual categorization process. Current theories and models suggest that this process comprises a hierarchy of different computations that transforms complex, high-dimensional inputs into lower-dimensional representations (i.e., manifolds) in support of multiple categorization behaviors. Here, we tested this hypothesis by analyzing these transformations reflected in dynamic MEG source activity while individual participants actively categorized the same stimuli according to different tasks: face expression, face gender, pedestrian gender, and vehicle type. Results reveal three transformation stages guided by the pre-frontal cortex. At stage 1 (high-dimensional, 50-120 ms), occipital sources represent both task-relevant and task-irrelevant stimulus features; task-relevant features advance into higher ventral/dorsal regions, whereas task-irrelevant features halt at the occipital-temporal junction. At stage 2 (121-150 ms), stimulus feature representations reduce to lower-dimensional manifolds, which then transform into the task-relevant features underlying categorization behavior over stage 3 (161-350 ms). Our findings shed light on how the brain's network mechanisms transform high-dimensional inputs into specific feature manifolds that support multiple categorization behaviors.